TWI293879B - Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino -imino -methyl)-phenylamion]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof - Google Patents

Description

1293879 (1) 玖, description of the invention (description of the invention should be stated: the technical field, prior art, content, embodiment and schematic description of the invention) TECHNICAL FIELD The present invention relates to the active substance 3-[(2-{[4 -(hexyloxycarbonylamino-imino-methyl)·phenylamino]-methyl}_1_methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino] a form of administration for oral administration of ethyl propionate and a pharmaceutically acceptable salt thereof. PRIOR ART The active material having the following chemical formula is known from WO 98/37075,

NH

This patent document discloses a compound having the effect of inhibiting thrombin action and prolonging the thrombin time, and its name is 1-methyl-2-[N-[4_(N-n-hexyloxycarbonyl)phenyl]- Amino-methyl]-benzoate also-5-yl-decanoic acid·Ν·(2-ρ ratio decyl)-Ν-(2-ethoxycarbonylethyl)-decylamine, the formula I The compound is a double prodrug of the compound of formula II 1293879 (2)

NH

That is, after entering the body, only the compound of formula I is converted to the active compound (i.e., the oxime compound). The main indication of this compound of formula I is to prevent deep vein thrombosis after hand street. The object of the invention is to provide an improved formulation suitable for oral use of the compound of formula I (which is also referred to hereinafter as the "active substance π". The surprising 1 is 'now found in solids The use of a pharmaceutically acceptable organic acid (which is water soluble at 2 ° C, > 1 g / 250 ml, preferably greater than 1 g / 160 ml at 25 ° C) can result in a significant improvement in oral formulations. Formulation·· 3-[(2-{[4_(hexyloxyamino-imino-methyl)-phenylamino]-methyl}-bumethyl-1H-benzimidazole-5- Carbon-based)-pyridylamino-propionic acid ethyl ester and pharmaceutically acceptable salts thereof. The pharmaceutically suitable acid for the purpose of the present invention is, for example, tartaric acid, ruthenic acid, citric acid 'Malic acid, methic acid and aspartic acid, and includes the unsynthesized and acid salts thereof. The acids particularly suitable for the purposes of the present invention are tartaric acid, fumaric acid, succinic acid and citric acid. A preferred embodiment of the article is a multiparticulate formulation wherein the individual particles are made as shown in Figure 1.

1293879 (3) Figure 1 shows a schematic structure of the pharmaceutical composition shown by a cross section suitable for preparing the granules of the pharmaceutical composition according to the present invention. The substantially beaded/spherical core region of the granule comprises or consists of the pharmaceutically acceptable organic acid. The next layer is then referred to as an insulating layer which isolates the acid core from the layer containing the active material. Next, the barrier layer is surrounded by a circular layer of the active material, which is then surrounded by a coating which increases the abrasion resistance and shelf life of the particles. An advantage of the formulation so produced is that the organic acid can be suitably spatially separated from the active material by the barrier layer. Another advantage of the granulation process as described above is that the organic acid will not dissolve in the solution until the formulation has been ingested, and then an acidic community climate is obtained which dissolves the active material. The core material used is a pharmaceutically acceptable organic acid (water solubility > 1 g / 250 liters at 20 ° C), for example, tartaric acid, butyl succinic acid, succinic acid, citric acid, Malic acid, glutamic acid and aspartic acid, and including hydrates and acid salts thereof, may be added with a small amount of a binder (1 to i% by weight, preferably 3 to 6% by weight), as needed. For example, if the starting acid is made by a disc accumulation method, a binder is required. If the method of use is extrusion or spheronisation, it is necessary to use other technical adjuvants (e.g., cytokines) in place of the binder. Pure (100%) acid can also be used as the starting material, with the proviso that the pure acid can be in a narrow range of particle sizes. The pharmaceutically acceptable organic acid used is preferably tartaric acid, trans-succinic acid, succinic acid or citric acid; more preferably tartaric acid. The following substances can be used as a binding agent: gum arabic or one selected from hydroxypropyl cellulose, 1293879 (4) propyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethyl A pyridone, a copolymer of N. ethylenepyrrolidone and vinyl acetate or a partially or wholly synthetic polymer of a combination of these polymers; preferably gum arabic. The spherical core material preferably has an average diameter of 0.4 to 1.5 mm. The pharmaceutically acceptable organic acid content of the core material is typically between 30% and 100%, which corresponds to between 20% and 90% of the finished granules (ie, the pharmaceutical composition). Preferably, it is between 20% and 80°/〇. In order to increase the durability of the finished product, it is preferred to coat the core or material with an insulating layer of a predominantly water-soluble pharmaceutically acceptable polymer prior to application of the active. Examples of such a water-soluble polymer include, for example, gum arabic or a partially or wholly synthetic polymer selected from the group consisting of propylcellulose, propylpropylmethylcellulose, methylcellulose, hydroxyethyl A cellulose, a methine cellulose, a polyvinylpyrrolidone, a copolymer of N-vinylpyrrolidone and ethyl acetate, or a combination of these polymers. Preferably, arbor gum or propyl propyl methylcellulose is used. If necessary, add a suitable plasticizer. Separating agent and pigment (for example, triethyl citrate, tributyl citrate, glycerol acetate, polyethylene glycol (plasticizer), talc, citric acid (separating agent), titanium oxide or iron oxide pigment (Pigment) The coating step of the water-soluble pharmaceutically acceptable polymer. The active material layer contains the active material (hexyloxycarbonylamino-imidomethyl)-phenylamino]-methyl}_i•methyl_1H•benzimidazole Icarbonyl^^哫_2_ Ethyl-amino]-propionic acid ethyl ester (BIBR 1〇48) or one of the pharmaceutically acceptable salts and binding agents thereof and optionally a separating agent. Active substance

1293879 (5) The methanesulphonate of the compound of the formula i is a ketone mixture comprising, for example, hydroxypropylcellulose, propylmethyl. Suitable for i, '〃, square, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polycellulose ethyl p-pyrrolidone, a copolymer of N-vinylpyrrolidone and vinyl acetate or > A composition of this polymer. Copolymers of propylcellulose or far N-vinylpyrrolidone are preferably used. The addition of the separating agent (e.g., ' talc or dream acid) prevents the particles from agglomerating as the process proceeds. The content of the active substance is from 5 to 60%, preferably from 1 to 50%, of the pharmaceutical composition. The optional outermost layer of the selected outermost layer of the filming agent, the plasticizer and, if desired, the pigment composition can be reduced when filled into the capsule. Suitable film formers include, for example, propylcellulose, hydroxypropylmethylcellulose, methylcellulose, polymers and copolymers of propylene and methacrylic acid and esters thereof, or combinations of these polymers Things. Suitable plasticizers include, in particular, triethyl citrate, tributyl citrate, triethylene glycol vinegar or polyethylene glycol. The pigment used may be, for example, a dioxins or an iron oxide pigment. The outermost coating layer is composed of hydroxypropylmethylcellulose and/or methylcellulose, and polyethylene glycol may be added as a plasticizer if necessary. The pellet can be prepared by the following method: The core material of the far acid is composed of the crystal of the specific organic acid used or more preferably by a spherical particle having a large amount of organic acid and having a desired size (which can be made by the chain) Lxu, Liang Technology is known and has been determined by the method of making). In more detail, the core material can be prepared by a disc method using a granulating plate or by an extrusion method/搓 round method. Then, the -10- 1293879 (6) core material thus obtained can be divided into portions of the desired diameter by screening. Suitable core materials have an average diameter of 0.4 to 1.5 mm, preferably 0.6 to 0.8 mm. First, the barrier layer is applied to the acid-containing core material. This step can be carried out by the following conventional methods: for example, an aqueous dispersion of the water-soluble pharmaceutically acceptable polymer can be applied using a fluidized bed, a coating tray or a conventional coating device (which can be plasticized as needed) Agent, separating agent and/or pigment). The product can then be screened if necessary. The active material is then applied from a dispersion comprising a binding agent and optionally a separating agent. The volatile dispersant can be removed during or after drying. Suitable binders in the dispersion may be, for example, propylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, a copolymer of N-vinylpyrrolidone and vinyl acetate or a combination of these polymers. Preferably, hydroxypropylcellulose or a copolymer of the N-vinylpyrrolidone and vinyl acetate is used. Suitable separating agents include, for example, talc or ground acid; talc is preferred. The dispersing agent may be, for example, ethanol, 2-propanol, propanol or a mixture of these solvents with each other or water, preferably 2-propanol. The active material can be applied to the core material by a known method known in the pharmaceutical arts (e.g., coating tray, conventional film coating apparatus or fluidized bed method). Further screening methods can then be performed. In order to reduce wear or to increase the life of the palm when it is transferred into the capsule, the system can be finally coated with a coating containing a conventional film-forming agent, a plasticizer and, if desired, a pigment. This step can be carried out by the conventional method previously described in the description of the application of the barrier layer. When a core material having an average diameter of 0.4·1.5 mm is used, the above method -11-1293879 can produce particles containing an active material which can then be filled, for example, into a hard capsule. In order to perform the steps, it is necessary to fill a plurality of these units equivalent to the desired dose into the hard capsule using a standard capsule filling machine. Suitable hard capsules include, for example, hard gelatin capsules or hard capsules containing hydroxypropyl methylcellulose (HPMC); preferably HPMC capsules. The pharmaceutical composition has an active substance content of 5% to 6%, preferably 1% to 5%, and the pharmaceutically acceptable organic acid is usually between 20% and 90%, preferably 20%. Between % and 80%. Embodiments Unless otherwise indicated, the percentages stated are generally % by weight. Unless otherwise specified, all information regarding the active substance content is relevant to the active base of the active substance (not to a particular salt). Tests In the preliminary test of test animals using a conventional lozenge containing the compound of the general formula I have been confirmed to have a high variable plasma content, and malabsorption I occurs in individual cases. The variability in the plasma content pattern was significantly reduced after administration of the formula 口服 compound in an oral solution form; and in these cases, no cases of malabsorption occurred. Tests have shown that at low p Η values, the compound of formula I can be quite adequately decomposed in water, whereas 'according to the definition of the European Pharmacopoeia (European Pharmacopoeia), at a pH above 5, the formula The i compound is substantially insoluble. Therefore, in one branch of the clinical trial, the volunteer is given a panic shunt (which produces a high gastric acid pH). For example, the bioavailability of the pharmaceutical compositions according to Examples 1 and 2 can be tested by comparison to conventional lozenges. To test the bioavailability, a clinical trial of the formulation made according to Example 1 for each of the 15 volunteers containing 1 50 879 (8) capsules containing 50 mg of active substance base was investigated for its bioavailability. In one of the treatments, the composition was orally administered to a volunteer without any prior treatment. In another branch of the treatment, the same volunteer was orally administered with 40 mg of squeaking bid (two times a day), which took 3 days to increase the pH of the stomach acid before oral administration of the composition; When the formulation according to the present invention is administered, the performance is treated with a pan-shrimp treatment.

The degree of absorption is determined by measuring the amount of excretion of the active metabolite of Formula II in the urine. The relative bioavailability was 94% on average after pretreatment with piperazine, compared to administration without any pretreatment. The relative bioavailability of a lozenge containing 50 mg of active substance (which does not contain a water-soluble organic acid) was formed according to the prior art under similar administration conditions, also after pretreatment with piperacazole (at this plasma concentration/ The area under the time curve is based on the benchmark) is 18%. The following list indicates the precise composition of the tablet used:

Ingredient mg/tablet Methanesulfonate of the compound of formula I 57.7 Lactose monohydrate 58.0 Microcrystalline cellulose 48.3 Clopavir _((^〇30〇^(1〇116) 3.4 Magnesium stearate 2.6 Polyethylene glycol 6000 0.56 Titanium dioxide 0.80 Talc 0.64 Hydroxypropyl methylcellulose 1.92 Iron oxide yellow 0.08 Total 174.0 -13 - 1293879 (9)

Thus, the relative bioavailability can be improved by about 5 coefficients by using the formulation according to the invention. A clinical trial of the bioavailability of the formulation prepared according to Example 2 for each of a total of 15 volunteers containing 50 mg of active substance per capsule was also performed. In one of the treatments, the volunteer was orally administered the composition on an empty stomach without any pre-treatment. In another branch of the treatment, the same volunteer was orally given 4 〇 〇 泛 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' When the formulation was invented, it was treated with a panic. The degree of absorption can be determined by measuring the amount of excretion of the active metabolite of the formula in the urine. The relative bioavailability was 76% on average after pre-treatment with piperazine, compared to administration without any pretreatment. The relative bioavailability of the lozenge containing 50 g of active substance (which does not contain a water-soluble organic acid) is formed according to the prior art under similar administration conditions, after pretreatment with piperacazole, according to the prior art. The area under the /time curve is the benchmark) is 18%. The following list indicates the exact composition of the tablet used: Ingredient mg/bonding agent Methanesulfonate of the compound of formula I 57.7 Lactose monohydrate 58.0 Microcrystalline cellulose 48.3 Crospovidone 3.4 Hard Magnesium citrate 2.6 — Polyethylene glycol 6000 0.56 Titanium dioxide 0.80 4(id> ¥石_ ' 0.64 Hydroxypropyl methyl sulphate 1.92 Iron oxide yellow 0.08 Total 174.0 -14-

1293879 (10) Thus, the relative bioavailability of the active substance can be improved by about 4 coefficients by using the formulation according to the present invention as compared to conventional formulations. The bioavailability of the two formulations according to the present invention is graphically represented in Figure 2 as compared to the tablet as described above and not administered with piperazine.

This clinical test shows another advantage of the formulation containing the compound of the general formula I according to the invention, which is to ensure the proper bioavailability of the active substance more than the conventional pharmaceutical preparation, and is mainly independent of the pH of the gastric acid, and thus The variation in the bioavailability of the active substance is reduced, and it can avoid malabsorption. Another advantageous property of the pharmaceutical composition according to the invention is that it is suitable for all patients, that is, the patients include drugs which increase the pH of the stomach acid by disease or by using normal physiological variability The increase in co-medication. The patient with the pH of the stomach acid. In each case, the oral dose is preferably from 25 to 300 mg of the active substance base (per capsule), more preferably from 50 to 200 mg, optimally from 75 to 150. Mg of the active substance base.

The preferred ratio of the acid to the active material is from about 0.9:1 to about 4:1, most preferably between about 1:1 and 3:1. Preferably, at least one equivalent acid is used per mole of the compound of formula I. The upper limit of about 4:1 (acid to active) is usually determined by the maximum acceptable size of the formulation in the desired dosage form (number of particles per gel capsule). The following examples are intended to illustrate the invention: -15- 1293879 (ii) Example core 3J ------ ——---- Composition percentage per capsule [亳克] Each capsule "mg" Insulation activity Material layer total - - 61.3 176.7 353.4 2.8 5.9 17.0 34.0 5.6 3.2 8.8 25.4 50.7 - 4.0 4.0 11.5 23.1 20,0 20.0 57.7* 115.3** 100.0 288.3 576.5 Tartaric acid arabin gum talc hydroxypropyl cellulose active substance (compound of formula I) Methanesulfonate) A total of *) corresponds to 50 mg of the compound of the formula 1 (living substance base) **) equivalent to 1 mg of the compound of the formula 1 (active substance base) a) containing tartaric acid Core material preparation method: Gum arabic 1 part by weight tartaric acid 20 parts by weight 1 part by weight of gum arabic is dissolved in 4 parts by weight of pure water at 50 ° C, and stirred. Then, 5 parts by weight of tartaric acid was dissolved in the solution and stirred. A crystal of 8.3 parts by weight of tartaric acid (having an average particle size of 〇 4 to 〇 6 耄) was placed in a suitable coating device equipped with an air inlet tube and an exhaust port, and then the disk was set to rotate. At 60, 80. (: At the temperature of the air inlet pipe, spray the tartar with a solution of tartaric acid and gum arabic at intervals of time and then spray it with a total of 6.7 parts by weight of powdered tartaric acid, so that about spherical particles are formed. -16- 1293879 (12)

The spherical tartaric acid core material was then dried in the rotating disk at an air inlet tube temperature of 60 ° 80 °C. The core material was fractionated using a tumbler screen with a perforated plate having a nominal mesh size of 0.6 and 0.8 mm. The portion of the product between 0.6 and 0.8 mm is used in the remaining steps of the process. b) isolation method composition of the core material containing tartaric acid: core material containing tartaric acid 23 parts by weight of gum arabic 1 part by weight talc 2 parts by weight, 1 part by weight of gum arabic dissolved in 6.7 parts by weight of 96% ethanol and 13.5 parts by weight of a mixture of pure water and stirred. Then, 2 parts by weight of talc was dispersed in the solution and stirred. In the flow boring machine, 23 parts by weight of the core material containing tartaric acid was sprayed by the bed under spray method at a temperature of 35 ° - 40 ° C at the air inlet tube by spraying the gum arabic and talc. The isolated core material containing tartaric acid was then dried in the circulating air dryer for 8 hours at 40 °C. To remove any chunks, the dried tartaric acid containing core material was screened by a screen having a nominal mesh size of 1.0 mm. Further processing is performed on the material portion having a particle size < 1 mm. c) Preparation of the active material layer -17- 1293879 (13) Composition: Isolated core material containing tartaric acid 91 parts by weight propylcellulose 5 parts by weight talc 4 parts by weight active material (BIBR 1048 methane Sulfonate) 25 parts by weight of hydroxypropylcellulose was dissolved in 168 parts by weight of 2-propanol and stirred, and then the active material and talc were dispersed in the solution and stirred. Spraying 91 parts by weight of the isolated core material containing tartaric acid in a fluidized bed processing apparatus at a temperature of 20 ° - 30 ° C at the air inlet tube by spraying the active material by the bed spray method . The particles containing the active material were then dried in the circulating air dryer at 35 ° C for 8 hours. In order to remove any chunks, the particles containing the active material can be screened by a sieve having a nominal mesh size of 1.25 mm. The material portion having a particle size < 1.25 mm is further processed. d) Method of filling into capsules In each case, the active substance particles containing one of 50 or 100 mg of active substance base are filled into hard gelatin capsules or HPMC capsules of size 1 or size by a capsule filling machine. . -18 - 1293879 (14)

Example 2 ------- Stone i ' Percentage of composition per capsule [亳克] Each capsule [mg] Core material _ Insulation active layer A total of 38.5 38.5 55.5 166.5 Acacia 1.9 1.7 3.6 5.2 15.6 Talc --- —. Hydroxypropylcellulose 3.5 6.4 _ 9.9 14.3 42.8 _ - 8.0 8.0 11.5 34.6 Active substance (methanesulfonate of the compound of formula I) Surface 40.0 40.0 57.7* 173.0** Total 100.0 144.2 432.5 *) Equivalent to 50 The compound of the formula I (active substance base) * * ) corresponds to 1 5 〇 mg of the compound of the formula I (active substance base) a) The composition of the core material containing tartaric acid: 1 part by weight of gum arabic 20 parts by weight of tartaric acid 1 part by weight of gum arabic was dissolved in 4 parts by weight of pure water at 50 ° C and stirred. Then, 5 parts by weight of tartaric acid was dissolved in the solution and stirred. 8.3 parts by weight of tartaric acid crystals (having an average particle size of 〇·4 to 0.6 mm) were placed in a suitable coating apparatus equipped with an air inlet tube and an exhaust port, and then the disk was set to rotate. Spraying the tartaric acid crystals with the solution of the tartaric acid and gum arabic at intervals of 60 ° - 8 (rC air inlet tube temperature) and then squirting with 6.7 parts by weight of powdered tartaric acid, thus forming an approximately spherical shape Granules. -19- 1293879

(15) The spherical tartaric acid core material is then dried in the rotating disk at a temperature of 60 ° _ 80 ° C air inlet tube. The core material was fractionated using a tumbler type screening machine (a perforated plate having a nominal mesh size of 〇·6 and 〇·8 mm). The portion of the product between 0.6 and 0.8 mm is used in other steps of the process. b) Isolation method consisting of core material containing tartaric acid: core material containing tartaric acid 23 parts by weight of gum arabic 1 part by weight talc 2 parts by weight 1 part by weight of gum arabic dissolved in 6.7 parts by weight of 96% ethanol and 13.5 Mix in parts by weight of pure water and stir. Then 2 parts by weight of talc was dispersed in the solution and stirred. In the fluidized bed processing apparatus, 23 parts by weight of the core material containing tartaric acid was sprayed with the dispersion of gum arabic and talc by the bed under spray method at an air inlet tube temperature of 35 ° · 40 ° C . The isolated core material containing tartaric acid was then dried in the circulating air dryer at 40 °C for 8 hours. In order to remove any lumps, the dried tartaric acid-containing core material was screened by a screen having a nominal mesh size of 1.0 mm. Further processing of the material portion having a particle size < 1 mm was performed. c) Method for preparing the active material layer -20- 1293879 Composition: Isolated core material containing tartaric acid

57 parts by weight, 1 part by weight, talc, 8 parts by weight of active material (methanesulfonate of BIBR 1048) 50 parts by weight of hydroxypropylcellulose dissolved in 3 3 5 parts by weight of 2-propanol, and After stirring, the active material and talc are dispersed in the solution and stirred. Spraying 91 parts by weight of the isolated core material containing tartaric acid in a fluidized bed processing apparatus at a temperature of 20 ° - 30 ° C at the air inlet tube by spraying the active substance with the dispersion of the active material. . The granules containing the active substance are then dried in the circulating air dryer for 8 hours at 35 ° C. In order to remove any lumps, the sieve may be selected by a sieve having a nominal mesh size of 1.25 mm. Particles of active substance. The material portion having a particle size < 1.25 mm is further processed. d) Method of filling into capsules In each case, the active substance particles containing one of 50 or 150 mg of the active substance base are filled into hard gelatin capsules or HPMC capsules of size 2 or size 0 by means of a capsule filling machine. Example 3 3-[(2-{[4_(Hexoxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl )-Pyridine·2·yl-amino]-propionic acid ethyl ester methane acid salt preparation method _; _ -21 - 1293879 (17)

Add 5 ml of ethyl acetate solution of 5.0 mM methanesulfonic acid to 3139 mg (5.0 mmol) 3-[(2-{[4-(hexyloxycarbonyl)) at ambient temperature with stirring. -Imino-methyl)-phenylamino]-methyl}-1.methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester A solution (as described in WO 98/3 7075) was prepared in 250 ml of ethyl acetate solution. After a few minutes, the product began to crystallize. At ambient temperature, it was stirred for another hour, then stirred for an additional hour, while using ice cooling, the precipitate was suction filtered, washed with about 50 ml of ethyl acetate and 50 ml of diethyl ether, and Dry at 50 ° C in a circulating air dryer. Theoretical yield: 94% Melting point: 178_179°C C34H4iN7〇5 x CH4SO3 (723.86) Elemental analysis: Calculated: C 58.07% Η 6.27% Ν 13.55% S 4.43% Found: 58.11% 6.30% 13.50% 4.48% .22 - 1293879 (18) Titles in the figures: Figure 1: The core material of the graphic structure of the pharmaceutical composition

Kernmaterial enthaltend organische Saure = containing machine Isolierschicht = insulation layer Wirkstoffschicht = active material layer Oberzug (optional) = coating film (optional) Figure 2: BIBR 1048 bioavailability ohne Pantoprazol = no pantoprazole mit Pantoprazol = have Pan shouting

Tablette == Lozenges

Kapsel = capsule

Bs.=Instance '

Claims (1)

I Wai replacement (October 96) n曰修(more) 正本, patent application scope 1. An oral pharmaceutical composition comprising at least a) - one or more at 20 ° C > 1 g / 250 ml of a water-soluble pharmaceutically acceptable organic acid consisting of or comprising a substantially spherical core material of one or more pharmaceutically acceptable organic acids, and b) a binding agent and, if desired, separation An active material layer of the agent, which is coated with the core material, wherein the active material is 3-[(2-{[4-(hexyloxycarbonylamino-imido-methyl)-phenylamino]] Methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester or a pharmaceutically acceptable salt thereof. 2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable organic acid is tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid or aspartic acid or a kind Its hydrate or acid salt. 3. The winter pharmaceutical composition according to claim 2, characterized in that the medically acceptable organic acid is tartaric acid, fumaric acid, citric acid or succinic acid. 4. The pharmaceutical composition according to item 3 of the patent application, characterized in that the pharmaceutically acceptable organic acid is tartaric acid. 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein 3-[(2-{[4-(hexyloxycarbonylamino)-imino-methyl) in the pharmaceutical composition )-phenylamino]-methyl}-1·methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester or the content of each of the salts thereof is 5 to 60%. 6. The pharmaceutical composition according to any one of claims 1 to 4, 83961-961012.doc 1293879 wherein the pharmaceutically acceptable organic acid is present in an amount of from 20 to 90%. The pharmaceutical composition according to any one of claims 1 to 4, wherein the binder is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methyl A copolymer of cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, N-vinylpyrrolidone and ethyl acetate, or a combination of these polymers. The pharmaceutical composition according to any one of claims 1 to 4, wherein the core material has an average particle size of 0.4 to 1.5 mm. 9. The pharmaceutical composition according to any one of claims 1 to 4, wherein the core material and the active material layer are composed of a water-soluble polymer, a suitable plasticizer, a separating agent, if necessary. The barrier layers composed of the pigments are separated from each other. 10. The pharmaceutical composition according to claim 9, wherein the water-soluble polymer is composed of gum arabic or a partially or fully synthesized polymer selected from the group consisting of: hydroxypropyl Cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, copolymer of N-vinylpyrrolidone and vinyl acetate or these polymers The combination. The pharmaceutical composition according to any one of claims 1 to 4, wherein the active substance-containing composition is filled into a hard capsule. 12. The pharmaceutical composition according to claim 11 wherein the active substance-containing composition is filled into a HPMC capsule. The pharmaceutical composition according to any one of claims 1 to 4, wherein 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenyl) is used. Amino]-mercapto 1-methyl-1H-benzimidazole-5-carbonyl)-pyridine-2- 83961-961012.doc 1293879 benzyl-amino]-propionic acid ethyl methane sulfonate as the activity substance. 14. A 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]]methyl}-1-indenyl-1H--containing for oral administration A method of pharmaceutical composition of benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate or a physiologically acceptable salt thereof, comprising the steps of: a) by a disk method One or more pharmaceutically acceptable organic acids (groups) (which at 20 ° C, water soluble > 1 g / 250 ml) are obtained on a granulation board or by extrusion/squeezing A binder or other technical adjuvant is required to form the core material, b) coated with one or more water-soluble pharmaceutically acceptable polymers, and optionally added with a plasticizer, a separating agent and/or a pigment. a layer to the core material, c) applying the active material to the dispersion containing the binder and optionally the separating agent, and simultaneously and/or subsequently drying to remove the dispersing agent, d) coating a coating as needed A coating film comprising a film forming agent, a plasticizer and optionally a pigment, and e) filling the thus obtained active substance pellet into a hard capsule. 15. 3-[(2-{[4-(Hexyloxycarbonylamino-imino-indenyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole- 5-Carbonyl)-pyridine. 2-Amino-amino]-propionic acid ethyl methanesulfonate. 16. A pharmaceutical composition comprising 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-indenyl 1-methyl-1 oxime] - Benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester methanesulfonate. 83961-961012.doc